Arylsulfonylformamidoximes

ABSTRACT

ARYLSUFONYLFORMAMIDIXIMES OF THE GENERAL FORMULA   (R1)N-C6H4-SO2-C(-NH2)=N-O-R   ARE USEFUL AS ANTIMICOROBIAL AGENTS, HYPOGLYCEMIC GENTS AND ANTIINFLAMMATORY AGENTS.

3,736,356 ARYLSULFONYLFORMAMIDOXIMES Uwe D. Treuner, Regensburg,Germany, assignor to E. R. Squibb & Sons, Inc., Princeton, NJ. NoDrawing. Filed Oct. 19, 1971, Ser. No. 190,693

Int. Cl. C07c 103/10 US. Cl. 260-562 R 11 Claims ABSTRACT OF THEDISCLOSURE Arylsulfonylformamidoximes of the general formula NOR S Oz-CNH: i n

are useful as antimicrobial agents, hypoglycemic agents andantiinfiammatory agents.

BRIEF SUMMARY OF THE INVENTION This invention relates to newarylsulfonylformamidoximes having the general formula /N O R s Oz-Cwherein R is hydrogen,

CO (CH R- CONHR or COCX R is hydrogen, halogen, lower alkyl, loweralkauoylamido R is halogen, lower alkyl, COOH, COO-lower alkyl S-loweralkyl, S-aryl, O-lower alkyl, O-aryl, NH N-(lower alkyl), NH(l0weralkyl), NH-aryl, or

L R is phenyl or lower alkyl; X is halogen; Y is CH 0, S, NH or N-loweralkyl; mis 1 to 4; and n is 1 to 3 and salts of the basic, salt formingmembers.

DETAILED DESCRIPTION OF THE INVENTION "United States Patent O 3,736,356Patented May 29, 1973 A preferred group of arylsulfonylformamidoximeswithin the above class have the formula NOR wherein R is hydrogen, CO(CHR -C'ONHR or R is hydrogen, halogen, lower alkyl (especially methyl andethyl) or lower alkanoylamido (especially acetamido);

R is halogen (especially chlorine and bromine), lower alkyl (especiallymethyl and ethyl), COOH 0r COO lower alkyl (especially C'OOCH and COOC HR is phenyl;

X is chlorine;

m is 1 or 2; and

n is 1.

The compounds of Formula I wherein R is a basic group form acid additionsalts with the common organic and inorganic acids. Particularly theseare compounds of Formula I wherein R is one of the nitrogen containingradicals.

These salts are acid addition salts formed from a variety ofpharmaceutically acceptable inorganic and organic acids, for example,hydrohalides (especially hydrochloride and hydrobromide), sulfate,nitrate, borate, phosphate, oxalate, tartrate, malate, citrate, acetate,ascorbate, succinate, benzenesulfonate, methanesulfonate,cyclohexanesulfamate and toluenesulfonate. The acid additions saltsfrequently provide a convenient means for isolating the product, e.g.,by forming and precipitating the salt in an appropriate menstruum inwhich the salt is insoluble, then after separation of the salt,neutralizing with a base such as barium hydroxide or sodium hydroxide,to obtain the free base of Formula I. Other salts may then be formedfrom the free base by reaction with an equivalent of acid.

The new compounds of Formula I wherein R is hydrogen are produced fromphenylsulfonyl cyanides of the (III) by treatment with hydroxylamine ora salt thereof, e.g., a hydrohalide such as the hydrochloride. Thereaction is efiected in an inert organic solvent, e.g., an alcohol suchas ethanol, at about room temperature. If a hydroxylamine salt is usedan alkali metal bicarbonate such as potassium bicarbonate is preferablypresent.

The phenylsulfonylformamidoxime, which is the product of the abovereaction, may then be converted to a compound of the invention wherein Ris other than hydrogen by reacting that product with an acid anhydride,as for example in Examples 5 and 6 which follow, or with acid halides ormixed acid ester halides as in Examples 7 and 8 which follow or with anisocyanate as in Example 10. The examples further illustrate theconditions of operation which are typical for the formation of thosetypes of products.

The starting materials of Formula III may be obtained by any of severalmethods available in the literature such as the following:

@soma BrCN Q 4 mammalian species such as rats, dogs and the like whengiven orally in dosages of about to 50 mg./kg./day, preferably 5 to 25mg./kg./ day, in single or 2 to 4 divided (B1)! l)n fin SO2CN See, forexample, Cox et al., Tetrahedron Letters No. 20 doses, as indicated bythe carageenan edema assay in rats.

39, 3351-3352 (1969); Pews et al., Iour. Chem. Soc. (Sec D, Chem.Commun.) 1969), 1187.

The new compounds of Formula I are useful as antimicrobial agents andmay be used to combat infections in animal species, such as mice, rats,dogs, guinea pigs and the like, due to organisms such as Trichomtmasvaginalis, Trichomonas foetus, Staphylococcus aureus, Salmonella schottmuelleri, Klebsiella pneumoniae, Proteus vulgaris, Escherichia coli orT richophyton mentagrophytes. For example, a compound or mixture ofcompounds of Formula I or physiologically acceptable acid addition salt(when formed) thereof may be administered orally to an infected animal,e.g., to a mouse, in an amount of about 5 to 25 mg. per kg. per day in 2to 4 divided doses. These may be conventionally formulated in a tablet,capsule or elixir containing about to 250 mg. per dosage unit, bycompounding the active substance or substances with the conventionalexcipient, vehicle, binder, preservative, flavor, etc., as called for byaccepted pharmaceutical practice. They may also be applied topically,e.g., to dermatophytosis in a guinea pig, in a lotion, salve or cream ata concentration of about 0.01 to 3 percent by weight.

They may also be used as surface disinfectants. About 0.01 to 1 percentby weight of any of these substances may be dispersed on an inert solidor in a liquid such as water and applied as a dust or spray. They may beincorporated also, for example, in a soap or other cleansing agent,e.g., a solid or liquid detergent, detergent composition, for example,in general cleaning, in cleaning dairy barns or equipment or cleaningfood handling or processing equipment.

The compounds of this invention are also hypoglycemic agents which areelfective in lowering blood sugar content in mammalian species such asmice, rats, rabbits, dogs or the like in a manner analogous totolbutamide. Some are particularly noteworthy in their long duration ofaction. For this purpose a compound or mixture of compounds of FormulaI, or non-toxic, physiologically acceptable acid addition salt (whenformed) may be administered orally or parenterally in a conventionaldosage form such as tablet, capsule, injectable or the like. A singledose, or preferably 2 to 4 divided daily doses, provided on a basis ofabout 1 to 50 mg. per kilogram per day, preferably about 2 to mg. perkilogram per day, is appropriate. These may be conventionally formulatedin an oral or parenteral dosage form by compounding about 10 to 250 mg.per unit of dosage with conventional vehicle, excipient, binder,preservative, stabilizer, flavor or the like as called for acceptedpharmaceutical practice.

The new compounds of this invention also have antiinfianunatoryproperties and are useful as antiinfiammatory agents, for example, toreduce local inflammatory conditions such as those of an edematousnature or resulting from proliferation of connective tissue in variousThe atcive substance may be utilized in compositions such as tablets,capsules, solutions or suspensions containing up to about 300 mg. perunit of dosage of a compound or mixture of compounds of Formula I orphysiologically acceptable acid addition salt (when formed). They may becompounded in conventional manner with a physiologically acceptablevehicle or carrier, excipient, binder, preservative, stabilizer, fiavor,etc. as called for by accepted pharmaceutical practice. Topicalpreparations containing about 0.01 to 3 percent by weight of activesubstance in a lotion, salve or cream may also be used.

The following examples are illustrative of the invention. Alltemperatures are expressed on the centigrade scale. Additionalvariations of the invention within the scope of Formula I may be madeaccording to the following procedures by suitable variations of thestarting materials.

EXAMPLE 1 1- (phenylsulfonyl) formamidoxime 0.76 g. (12 mmol.) ofhydroxylamine hydrochloride are added to 1.6 g. (10 mmol.) ofbenzenesulfonyl cyanide in 15 ml. of absolute ethanol. The mixture isstirred at room temperature and 1.05 g. (12 mmole) of sodium bicarbonateare added in small portions. This is stirred ior about two hours, theprecipitate is filtered under suction and then washed thoroughly withwater. The addi tion of water to the ethanolic filtrate yieldsadditional product. The crude product is crystallized from n-butanol. 1gm. of white crystalline 1-(phenylsulfonyDformamidoxime is obtained,M.P. 108 (explosive).

EXAMPLE 2 1- (p-chlorophenylsulfonyl) formamidoxime White crystalline1-(p-chlorophenylsulfonyl)formamidoxime, M.P. 7375 (dec.) is obtained bythe procedure of Example 1 by substituting an equivalent amount ofp-chlorophenylsulfonyl cyanide for the benzenesulfonyl cyanide.

EXAMPLE 3' 1- (p-toluenesulfonyl formamidoxime White crystallinel-(p-toluenesulfonyl)formamidoxime, M.P. -83 (dec.) is obtained by theprocedure of Example 1 by substituting an equivalent amount ofp-toluenesulfonyl cyanide for the benzenesulfonyl cyanide.

EXAMPLE 4 l-[ (p-acetamidophenyl)sulfonyl1formamidoxime Whitecrystalline l [(P acetamidophenyl]sulfonyl) for-mamidoxime M.P. (dec.)is obtained by the procedure of Example 1 by substituting an equivalentamount of (p-acetamidopheuyl)sulfonyl cyanide for the benzenesulfonylcyanide.

EXAMPLE 5 1- (phenylsulfonyl -O- chloro acetyl formamidoxime 2 g. mmol.)of 1-(phenylsulfonyl)formamidoxirne dissolved in 50 ml. of absolutetetrahydrofuran are treated with 1.9 g. (11 mmol.) of chloroaceticanhydride in 10 ml. of tetrahydorfuran. The temperature rises and awhite precipitate of l-(phenylsulfonyl)-O-(chloroacetyl)formamidoximeforms. After stirring for one half hour, the product is filtered undersuction, washed with ether and then crystallized from methylene glycolin the form of white needles, M.P. 190 (dec.), yield 2.8 g.

EXAMPLE 6 1-(phenylsulfonyl)formamidoxime-O-succinic acid mono ester 2g. (10 mmol.) of l-(phenylsulfonyl)formamidoxime are dissolved in 50 ml.of dioxane and refluxed for 1 hour with 1.2 g. (12 mmol.) of succinicanhydride. The white product 1-(phenylsulfonyl)formamidoxime O succinicacid monoester crystallizes and is recrystallized in the form of whitecrystals from methylene glycol, M.P. 176- 178.

EXAMPLE 7 1- (phenylsulfonyl form amidoxime-O-malonic acid methyl ester5 g. (25 mmol.) of 1-(phenylsulfonyl)formamidoxime are dissolved in 100ml. of absolute dioxane, treated with 3.2 g. (40 mmol.) of pyridine and5 g. (25 mmol.) of malonic acid methyl ester chloride are slowly addeddropwise with stirring and cooling. The progress of the reaction isfollowed with thin layer chromatography. At the end of the reaction, thesolvent is removed under vacuum and the residue is taken up with water,whereupon the product crystallizes. The product, l-(phenylsulfonyl)formamidoxime-O-malonic acid methyl ester, is recrystallized fromethanol to obtain 2 g. of cream colored crystals, M.P. 156-159 (dec.).

EXAMPLE 8 1- phenylsulfonyl) -O- (4-chlorobutyryl) formamidoxime 2.0 g.(10 mmol.) of l-(phenylsulfonyl)formarnidoxime and 0.8 g. (10 mmol.) ofpyridine are dissolved in 50 ml. of tetrahydrofuran and 1.55 g. (11mmol.) of 4- chlorobutyryl chloride are added slowly dropwise withstirring. After a short time, the product, l-(phenylsulfonyl)-O-(4chlorobutyryl)formamidoxime, crystallizes. It is recrystallized frommethylene glycol to obtain 3 g. of white needles, M.P. 185 (dec.).

EXAMPLE 9 1- phenylsulfonyl) -O- trichloroacetyl) formamidoximel-(phenylsulfonyl)-O-(trichloroacetyl)formamidoxime, M.P. 160 (dec.) isobtained by the procedure of Example 5 by substituting an equivalentamount of trichloroacetic anhydride for the chloracetic anhydride.

EXAMPLE 10 1- (phenylsulfonyl) formamidoxime-O-earb anil ate 2 g. mmol.)of 1-(phenylsulfonyl)formamidoxime are dissolved in ml. of toluenetreated with 1.2 g. of phenylisocyanate and refluxed for one hour. 1.9'g. of a white crystalline 1 (phenylsulfonyl)formamidoxime-O- carbanilateare obtained as a precipitate which is recrystallized from methyleneglycol-water, M.P. 193 (dec.).

The following additional compounds are prepared by the method ofExamples 1 and 5 by substituting for the benzenesulfonyl cyanide theappropriately substituted analog in the procedure of Example 1 and thenusing the product thus obtained in the procedure of Example 5,substituting for the chloracetic anhydride the appropriately substitutedacid anhydride NOR S0a-O\ 011 NHz Example R R n 11 CCH2CHa H 12(['[JCHz-Br H 1 1e (3-OOl p-CH; 1

14 fi-CHr-COOCZHA! H 1 15 Same as above p-CHs 1 p-C2H CONH 1 17C-CHz-OOOOHa p-Cl 1 18 fiF-CHrOCzHs 3,4,5-CH3 3 19 p-CH: 1

1-CH2-0 O C-CHz-N fiJ-CHz-N N-OH; O

22 (fi-GHrCl p-CEh-O-Cl 2 E-CH -N NH CCH2-N S H 26 fi3CH2-CHzS-CH3 H 1(|)i-CH2CH2-S O 28 H 3,4,5-Dl 3 29 fi-CHz-NH3 p-CH; 1

30 iCICH;;CHzNHCzH H 1 31 (fi-CH2N(CH3)2 H 1 32 fiCHOHa H 1 33 fi-NHC Hao,p-Cl 2 fi Q O 1 Also HCl salt.

(R1)- wherein R is hydrogen; R is hydrogen, halogen, lower alkyl orlower alkanoylamido; and n is 1 to 3.

or salts thereof with pharmaceutically acceptable acids.

2. A compound as in claim 1 wherein R is hydrogen; R is hydrogen,halogen, lower alkyl or lower alkanoylamido; and n is 1.

3. A compound as in claim 1 wherein R is hydrogen.

4. A compound as in claim 1 wherein R is hydrogen.

5. A compound as in claim 1 wherein R and R are both hydrogen.

6. A compound as in claim 1 wherein R is hydrogen, R is halogen and n is1.

7. A compound as in claim 6 wherein the halogen is chlorine.

8. A compound as in claim 1 wherein R is hydrogen, R is lower alkyl andn is 1.

9. A compound as in claim 8 wherein the lower alkyl group is methyl.

10. A compound as in claim 1 wherein R is hydrogen, R is loweralkanoylarnido and n is 1.

11. A compound as in claim 10 wherein the lower alkanoylamido group isacetamido.

References Cited UNITED STATES PATENTS 3,334,137 8/1967 Bruderlein260564 G BERNARD HELFIN, Primary Examiner G. A. SCHWARTZ, AssistantExaminer US. Cl. X.R.

260-243 B, 247.1, 268 MK, 293.73, 343.7, 470, 501.12, 501.14, 516, 564G, 999

